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Anti-CD14 treatment in patients with severe COVID-19: Clinical and biological effects in a Phase 2 randomized
F Linzee Mabrey1, Thomas R Martin1, Carolyn S Calfee2
1Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
Background And Research Question:
CD14-dependent innate immunity contributes to poor outcomes in COVID-19 pneumonia. We tested the clinical and biological efficacy of a blocking monoclonal antibody to CD14 (IC14) for treatment of severe COVID-19 pneumonia and the utility of a biomarker of CD14 pathway activation in predicting outcome.
Study Design And Methods:
We report a preplanned secondary analysis of the I-SPY COVID Trial, which enrolled hospitalized patients with severe COVID-19 pneumonia at 19 medical centers in the U.S. who required high-level respiratory support. Participants were randomized to receive either intravenous IC14 (4 mg/kg on Day 1, then 2 mg/kg on Days 2-4) (N=67) or standard care (N=76). Primary endpoints included time-to-recovery, defined as the first two-day period on ≤6L/min O2, and mortality. In predefined secondary analyses, we tested the association between IC14 treatment and mortality in patients with high or low baseline plasma presepsin (sCD14-ST), a biomarker of CD14 pathway activity, and the effects of IC14 on plasma biomarkers of pharmacodynamics, injury and inflammation.
Results:
IC14 treatment did not improve time-to-recovery or 28-day mortality in the overall population, and the trial was stopped due to meeting futility criteria for the time-to-recovery endpoint. However, a predefined sub-group analysis showed that IC14 treatment was associated with a numerical reduction in 28-day mortality in participants with high (above median) baseline presepsin levels (N=47) [Hazard Ratio for mortality (HRm)): 0.52, 95% credible interval (CrI): 0.22-1.22, posterior probability HRm<1 (Pr (HRm<1|Data))=0.93]. IC14 treatment increased plasma sCD14, a pharmacodynamic marker and decreased plasma inflammatory biomarkers, including IL-8, RAGE, VEGF, and presepsin.
Interpretation:
Although IC14 treatment did not improve overall clinical outcomes, this new secondary analysis shows that IC14 had the expected pharmacodynamic and biological effects, and that baseline plasma presepsin concentrations may identify patients likely to respond to IC14 treatment. Further trials are needed to determine the efficacy of IC14 treatment in acute lung injury and the value of presepsin to identify patients most likely to respond.
Clinical Trial Registration If Applicable:
Clinicaltrials.gov: NCT04488081.
Insights
This study investigated IC14, a CD14 antibody, for severe COVID-19 pneumonia. While not improving overall outcomes, IC14 showed potential in patients with high presepsin levels, suggesting it as a predictive biomarker.
Area of Science:
- Immunology
- Infectious Diseases
- Clinical Trials
Background:
- CD14-dependent innate immunity is linked to severe COVID-19 pneumonia outcomes.
- Investigating treatments targeting CD14 is crucial for managing severe respiratory infections.
Purpose of the Study:
- To evaluate the clinical and biological efficacy of IC14, a CD14-blocking antibody, in severe COVID-19 pneumonia.
- To assess the utility of plasma presepsin (sCD14-ST) as a biomarker for predicting treatment response.
Main Methods:
- A secondary analysis of the I-SPY COVID Trial involving hospitalized patients with severe COVID-19 pneumonia requiring respiratory support.
- Randomized controlled trial comparing intravenous IC14 to standard care, with predefined subgroup analyses based on baseline presepsin levels.
Main Results:
- IC14 did not improve time-to-recovery or 28-day mortality in the overall patient population.
- A subgroup analysis indicated a numerical reduction in 28-day mortality for patients with high baseline presepsin (HRm: 0.52).
- IC14 demonstrated expected pharmacodynamic effects, increasing sCD14 and decreasing inflammatory biomarkers.
Conclusions:
- IC14 treatment did not yield overall clinical benefits for severe COVID-19 pneumonia.
- Baseline plasma presepsin may identify patients who could potentially benefit from IC14 treatment.
- Further research is warranted to confirm IC14 efficacy in acute lung injury and the role of presepsin as a predictive biomarker.
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